The application seeks funding of studies focused on determining whether differential genetic PBL susceptibility to certain HIV strains plays a role in differential HIV transmission ratio and/or disease progression and understanding the molecular mechanisms underlying differential PBL susceptibility. Our previous studies have shown that PBLs from different donors exhibit differential susceptibility to productive infection by certain strains of HIV- 1, and that this differential PBL susceptibility appears to be genetically determined. The overall goals of this project are to further characterize differential PBL susceptibility to HIV by: (1) determining whether the degree of PBL susceptibility plays a role in vivo in determining the establishment of HIV infection or the rate of disease progression; and (2) determining the molecular mechanism by which "resistant" PBLs restrict productive infection by HIV. To determine if PBL genetic resistance to HIV is playing a role in the human population, we will study the susceptibility of PBLs from subjects who appear to manifest some element of resistance to HIV. These include long-term uninfected sexual partners of HIV-positive individuals and long-term infected subjects with high CD4 counts. These cohorts are already in place at various centers around the country and collaborations have been established with two of these centers. The studies of the molecular mechanisms of restriction will determine the step(s) in the replication cycle of HIV that is blocked in resistant PBLs, the viral determinant(s) of restriction, and the frequency of 2 types of restriction among many resistant PBL-HIV strap pairs. Understanding the molecular mechanisms by which "resistant" PBLs restrict infection by HIV will not only help in understanding this genetic trait, and possibly differential infection outcomes, but might lead to better understanding of HIV replicatory needs and of essential interactions between the virus and the host cell. It also might point to new approaches for anti-HIV therapy.